Androstane compounds containing trifluoro aliphatic substituents in the 2-position



United States Patent ANDROSTANE CUMPGUNDS CGNTAHNENG TRE- FLUGROALEHATHC SUBSTITUENTS IN THE 2-P@HTION Marcel Harnik, Morristown, Tenn,assignor to Cherrietron Corporation, Chicago, 21., a corporation ofDelaware No Drawing. Filed .luly 13, 1961, Ser- No. 123,63@

8 Claims. (Ci. ass-397.4)

This invention relates to androstane compounds of the following generalformula and to the production thereof:

OR CH H wherein R is a member of the group consisting of hydrogen andlower alkanoyl radicals such as formyl, acetyl, propionyl and butyrylradicals and X is a member of the group consisting of trifiuoroacetyl,2,2,2-trifluoro-1- acetoxyethylidene, 2,2,2-trifluoro-l-hydroxyethyl,2,2,2- trifiuoro 1 acetoxyethyl, 2,2,2-trifiuoroethylidene, and2,2,2-trifiuoroethyl radicals.

The compounds of this invention have adrenocortical activity and areuseful in the relief of inflammation of rheumatoid arthritis and similarcollagen and allergic conditions. They have particular utility ininducing thymolytic corticoid activity in mammals and can be appliedparenterally in aqueous suspensions or in innocuous organic solvents.They are thus useful in supplementing the cortical hormone production ofmammals without the side effects of the progestational hormones. Thesecompounds are also useful as intermediates in the synthesis ofadrenocorticoid compounds.

It is an object of this invention to provide new androstane compoundswhich have useful physiological activity. It is a further object toprovide efiicient methods for producing such compounds from availablesteroids. Another object is to provide androstane compounds havingfluorinated aliphatic radicals in the 2-position which are useful asadrenocorticoids. These and other objects are apparent from and areachieved in accordance with the following disclosure.

The compounds of this invention are produced fromandrostane-17-ol-3-one. The first step is the condensation ofandrostane-17-ol-3-one with an alkyl ester of trifiuoroacetic acid, ofdifluoroacetic acid or of monofluoroacetic acid, in the presence of analkaline condensing agent such as an alkali metal hydride or an alkalimetal alkoxide in an inert solvent. The condensation is preferablyconducted in a nonoxidizing atmosphere at a temperature in the range of50150 C. By this procedure a triiiuoroacetyl, difluoroa-cetyl ormonofluoroacetyl radical is introduced at the 2-position of=androstane-17-ol-3-one. The tri-, dior monofiuoroacetylandrostanolonecan then be reacted with an alkanoic acid anhydride, preferably in thepresence of a basic solvent such as pyridine, quinoline ordimethylaniline, to form an enol alkanoate from the fi-diketone which isformed by the introduction of the substituted acetyl radical at the2-position of the androstanolone. The trifluoroacetyl radical in the2-posit-ion can be hydrogenated, for example, with a noble metalcatalyst, to form a 2,2,2-trifluoro-l-hydroxyethyl radical, which can beacylated, for example, with acetic anhydride or chloride, to form a2,2,2-trifluoro-1-acyloxyethyl radiice.

cal. The 2,2,2-trifluoro-l-hydroxyethyl radical in the 2-position ofandrostane-l7-ol-3-one can be dehydrated, for example, with boilingconcentrated formic acid or alkaline earth silicates, to thecorresponding 2,2,2-trifluoroethylidene radical and the latter can behydrogenated to a trifluoroethyl radical.

The invention is disclosed in further detail by means of the followingexamples which are provided to illustrate the invention without limitingit thereto. It will be ap parent to those skilled in the art thatvarious modifications in reaction conditions, reagents and equivalentmaterials can be made without departing from the invention hereindisclosed.

EXAMPLE 1 2 -Triflu0r0acety lamlroslane-l -01-3 -One OH CH3 I A mixtureof 1.257 g. of androstane-17p-ol-3-one, 30 ml. of dry benzene, 0.6 g. ofsodium methoxide and 2 ml. of ethyl trifluoroacetate was refluxed slowlyunder nitrogen with stirring. The mixture was cooled, treated with cold5% hydrochloric acid and stirred until all the solid dissolved. Thebenzene layer was separated, washed with water and with saturated NaClsolution, dried and evaporated. The residue of2-trifluoroacetylandrostane-l7B- ol-3-one was dissolved in ether andagitated with 10% KOH solution. The white precipitate of the potassiumsalt of Z-triiiuoroacetylandrostane--01-3-one was separated, washed withwater and with ether, suspended in fresh ether and agitated with cold 5%hydrochloric acid until the solid dissolved. The ether layer wasseparated, washed with water and with saturated NaCl solution, dried andevaporated. The residue of crystalline2-triiiuoroacetylandrostane-17,8-ol-3-one amounted to 0.947 g., lVLP.123.5-127" C. Its LR. absorption spectrum had peaks at 6.13 and 6.33microns.

EXAMPLE 2 2- (2,2,2-Triflu0ro-]-Hydr0xyethylidene)Androstane-17,8-0l-3-0ne Diacetate CFaCO- 650 mg. ofZ-trifluor'oacetylandrostane-17,B-ol-3-one was dissolved in 3 ml. ofpyridine and 2 ml. of acetic anhydride and left at room temperature for16 hours. The solution was evaporated in vacuo on a steam bath and thesolid residue was tritura-ted with cold methanol and filtered. There wasobtained 0.35 g. of 2-(2,2,2-trifluoro-l-hydroxyethylidene) androstane17B ol-3-one diacetate, MP. 157.5-158.5 C. Its LR. absorption spectrum(KBr) had peaks at 5.55, 5.61, 5.72, 5.88 and 6.03 microns. Its UV.absorption spectrum had a maximum at 263 millimicrons (E=6,880). Itsoptical rotation was 113 3 On standing 2-(2,2,2-trifluoro 1hydroxyethylidene)- androstane-l7p-ol-3-one diacetate hydrolyzed to2-trifluoroacetylandrostane-l7,8-ol-3-one acetate, M.P. l- 105 C.

OAc CH3 onoo- Its LR. absorption spectrum had peaks at 5.80, 6.22 and6.40 microns.

EXAMPLE 3 2-(2,2,2-Trifluoroe1-Hydroxyethyl)Androstane- Heme-one The2-trifluoroacetylandrostane-17,8-ol-3-one prepared from 24 g. ofandrostane-17fi-ol-3-one by the method of Example 1 was dissolved in 200ml. of methanol and was hydrogenated at room temperature and 4050p.s.i.g. for 18 hours in the presence of 10 g. of 5% palladiumcharcoalcatalyst. The mixture was filtered and the filtrate evaporated. Theresidue of 2-(2,2,2 trifluoro-l-hydroxyethyl)androstane-l7fi-ol-3-onewas crystallized from aqueous methanol; yield 2.59 g., M.P. 98 C. Ondilution with water and refrigeration, the mother liquor gave 6 g. ofcrystalline product of M.P. 95 C. The combined crops onrecrystallization from 60% aqueous methanol gave 7.73 g. of solvatedprisms. On further recrystalliza- :tion from 80% methanol and drying invacuo at 120 C. for several hours, the pure2-(2,2,2-trifluoro-l-hydroxyethyl)androstane-l7fi-ol-3-one innon-solvated form was obtained, M.P. 149-151 C. Its LR. absorptionspectrum had peaks at 2.88 and 5.91 microns.

EXAMPLE 4 200 mg. of 2-(2,2,2-trifluoro-l hydroxyethyl)androstane-17fl-ol-3-one dissolved in 2 ml. of pyridine and 2 ml. ofacetic anhydride was kept at room temperature for 15 hours. The solutionwas diluted with ice and water and the precipitate of the diacetate wasrecrystallized from pentane. 2 (2,2,2trifiuoro-l-hydroxyethyl)androstanel7fi-ol-3-one diacetate melted at124-125" C. and its LR. absorption spectrum (KBr) had peaks at 5.64 and5.70 microns.

4- EXAMPLE 5 2- (2,2,2-Triflu0r0ethy lidenyl) Androstane- 1 7,8-01-3-0neF ormate 00011 on? OF3O]E[ 5.70 grams of 2-(2,2,2 trifluoro lhydroxyethyl)- androstane-17 fl-ol-3-one was dissolved in m1. of 98%formic acid and refluxed for 15 minutes. Ice and water were added and acrystalline precipitate of 2-(2,2,2-tri fiuoroethylidenyl)androstane17,8 o1 3 one formate formed on standing; yield 5.03 g. Onrecrystallization from aqueous methanol the product melted at 123- 125C.

EXAMPLE 6 2a-(2,2,2-Triflu0r0ethyl)Androstane- 17,8-Ol-3-One Acetate OAcCH OFBGHT dryness in vacuo and the crystalline Zea-(2,2,Z-t-Ilfl11010-ethyl)an-drostane-l7fl-ol-3-one acetate was separated and recrystallizedfrom methanol; M.P. 112.5114.5 C.

What is claimed as new and desired to be secured by Letters Patent ofthe United States is:

1. An androstane compound of the formula CH CH3 OR wherein R is a memberof the group consisting of hydrogen and lower alkanoyl radicals and X isa member of the group consisting of trifiuoroacetyl,2,2,2-trifluoro-lacetoxy-ethylidene, 2,2,2-trifluoro-l-hydroxyethyl,2,2,2- trifiuoro-l-acetoxyethyl, 2,2,2-trifluoroethylidene, and 2,2,2-trifiuoroethyl radicals.

2. A compound as defined by claim 1 wherein R is hydrogen and X istrifiuoroacetyl.

3. A compound as defined by claim 1 wherein R is acetyl and X is2,2,2-trifluoro-l acetoxyethylidene.

3,096,352 5 6 4. A compound as defined by claim 1 wherein R is 8. Acompound as defined by claim 1 wherein R is acetyl and X istrifluoroacetyl. acetyl and X is 2,2,2-trifluoroethy1 with theor.-configura- 5. A compound as defined by claim 1 wherein R is hytidrogen and X is 2,2,2-trifluoro-l-hydroxyethyl.

6. 1A compound as defined by claim 1 wherein R is 5 References Cited inthe file of this patent acety and X is 2,2,2-trifluoro-l-acetoxyethyl.

7. A compound as defined by claim 1 wherein R is UNITED STATES PATENTSformyl and X is 2,2,2-trifluoroethylidene. 3,013,032 Nathan Dec. 12,1961

1. AN ANDROSTANE COMPOUND OF THE FORMULA